Prostate cancer is the most commonly diagnosed cancer in American men and the second most common cause of death from cancer in American men.
Androgen withdrawal, by castration or through the use of an anti-androgenic drug, is the preferred treatment method for prostate cancer.
Bicalutamide (casodex) is a relatively potent, orally active anti-androgenic drug. Approximately 80% of the prostate cancer patients treated with bicalutamide respond to the treatment; however, most patients eventually relapse.
Prostate cancer, like other cancers, can be viewed as a breakdown in the communication between tumor cells and their environment, including their normal neighboring cells. Growth-stimulatory and growth-inhibitory signals are routinely exchanged between cells within a tissue. Normally, cells do not divide in the absence of stimulatory signals, and, likewise, will cease dividing in the presence of inhibitory signals. In a cancerous or neoplastic state, a cell acquires the ability to xe2x80x9coverridexe2x80x9d these signals and to proliferate under conditions in which a normal cell would not grow.
In general, tumor cells must acquire a number of distinct aberrant traits in order to proliferate in an abnormal maimer. Reflecting this requirement is the fact that the genomes of certain well-studied tumors carry several different independently altered genes, including activated oncogenes and inactivated tumor suppressor genes.
In addition to abnormal cell proliferation, cells must acquire several other traits for tumor progression to occur. For example, early on in tumor progression, cells must evade the host immune system. Further, as tumor mass increases, the tumor must acquire vasculature to supply nourishment and remove metabolic waste. Additionally, cells must acquire an ability to invade adjacent tissue. In many cases cells ultimately acquire the capacity to metastasize to distant sites.
It is apparent that the complex process of tumor development and growth must involve multiple gene products. It is therefore important to define the role of specific genes involved in tumor development and growth and identify those genes and gene products that can serve as targets for the diagnosis, prevention and treatment of cancers.
In the realm of cancer therapy it often happens that a therapeutic agent that is initially effective for a given patient becomes, overtime, ineffective or less effective for that patient. The very same therapeutic agent may continue to be effective over a long period of time for a different patient. Further, a therapeutic agent which is effective, at least initially, for some patients is completely ineffective or even harmful for other patients. Accordingly, it would be useful to identify genes and/or gene products that represent prognostic markers with respect to a given therapeutic agent or class of therapeutic agents. It then may be possible to determine which patients will benefit from particular therapeutic regimen and, importantly, determine when, if ever, the therapeutic regime begins to lose its effectiveness. The ability to make such predictions would make it possible to cease a therapeutic regime which has lost its effectiveness well before its loss of effectiveness becomes apparent by conventional measures.
The invention features methods for selecting and monitoring the effectiveness of therapeutic agents used for the treatment of prostate cancer. The invention also features methods for identifying novel therapeutic agents for the treatment of prostate cancer. The invention also features methods and compositions diagnosing prostate cancer and methods and compositions for preventing, treating, and diagnosing prostate cancer.
The invention is based, in part, on the identification of two classes of differentially regulated genes: 1) genes that are more highly expressed in prostate cancer cells treated with testosterone than in untreated prostate cancer cells; and 2) genes that are more highly expressed in prostate cancer cells treated with bicalutamide, an anti-androgenic compound, than in untreated prostate cancer cells. Genes which are more highly expressed in testosterone-treated prostate cancer cells than untreated prostate cancer cells are listed in Table 1 (SEQ ID NOS:1-40 and 86-130). Genes which are more highly expressed in bicalutamide-treated prostate cancer cells than untreated prostate cancer cells are listed in Table 2 (SEQ ID NOS:41-85 and 131-191).
By examining the expression of one or more of these identified genes in a sample of prostate cancer cells, it is possible to determine whether a selected compound, e.g., an anti-androgenic compound, can be used to treat the prostate cancer. Importantly, this determination can be made on a patient by patient basis. Thus, one can determine whether or not a particular prostate cancer treatment is likely to benefit a particular patient. The invention also features methods for determining whether a particular prostate cancer has become refractory to treatment with an anti-androgenic compound or other therapeutic agent.
The invention also features diagnostic methods and prognostic methods which can be used to identify patients having or at risk for developing prostate cancer. The identified differentially expressed genes whose expression is increased in the presence of testosterone and/or the products of such genes can be used to identify cells exhibiting or predisposed development of prostate cancer thereby diagnosing individuals having, or at high risk for developing, prostate cancer. The detection of the differential expression of identified genes can be used to select therapies before the benign cells attain a malignant state and to design a preventive intervention in pre-neoplastic cells in individuals at high risk.
In the various methods of the invention, gene expression can be measured at the mRNA or protein level. Alternatively, expression can be measured indirectly by measuring the activity of the protein encoded by the identified gene.
The differentially expressed genes identified herein are potential targets for the development of therapeutic compounds. Genes that are expressed at a higher level in prostate cancer cells in the presence of testosterone than in the absence of testosterone are identified. Because testosterone is required for growth and survival of prostate cancer cells, genes whose expression is increased in the presence of testosterone are potential therapeutic targets. Thus, identifying compounds which reduce the expression of such a gene or reduce the activity of the product of such a gene forms the basis for the development of new therapeutic agents. In addition, as noted above, increased expression of these genes can serve as a prognostic or diagnostic indicator of prostate cancer. Moreover, where increased expression of these genes is observed during the course of a therapy, it can be expected that the therapy is or has become relatively ineffective.
Also identified are genes that are expressed in prostate cancer cells at a high level in the presence of the anti-androgenic drug bicalutamide than in the absence of bicalutamide. Because bicalutamide is known to inhibit the growth of prostate cancer cells, genes whose expression is increased in the presence of bicalutamide are potential therapeutic targets. Thus, identifying compounds which increase the expression of such a gene or increase the activity of the product of such a gene forms the basis for the development of new therapeutic agents. In addition, increased expression of these genes can serve as a indicator that a given therapy is effective.
The invention provides methods for the identification of compounds that modulate the expression of genes or the activity of gene products involved in prostate cancer as well as methods for the treatment of prostate cancer. Such methods can, for example, involve the administration of such modulatory compounds to individuals exhibiting symptoms or markers of prostate cancer.
This invention is based, in part, on systematic search strategies coupled with sensitive and high throughput gene expression assays, to identify genes differentially expressed in prostate tumor cells treated with different drugs. The search strategies and assays used herein permit the identification of all genes, whether known or novel, which are differentially expressed in, e.g., testosterone-treated prostate cancer cells relative to untreated prostate cancer cells.
This comprehensive approach and evaluation permits the discovery of novel genes and gene products, as well as the identification of an array of genes and gene products (whether novel or known) that are influenced by drugs and natural products which are known to influence the growth and survival of prostate cancer cells. Thus, the present invention makes possible the identification and characterization of targets useful for rationale drug design and for the prognosis, diagnosis, monitoring, treatment, and prevention of prostate cancer.
In some respects the differentially expressed genes described herein can be used in the same manner and prostate specfic antigen, a commonly used marker for prostate cancer and pre-cancerous conditions related to prostate cancer.
xe2x80x9cDifferential expression,xe2x80x9d as used herein, refers to both quantitative, as well as qualitative, differences in the expression pattern of a gene in tumor cells treated with a particular drug and untreated tumor cells. Differentially expressed genes can represent xe2x80x9cfingerprint genes,xe2x80x9d and/or xe2x80x9ctarget genes.xe2x80x9d
xe2x80x9cFingerprint gene,xe2x80x9d as used herein, refers to a differentially expressed gene whose expression pattern can be utilized as part of a prognostic or diagnostic marker for the evaluation of prostate cancer or which, alternatively, can be used in methods for identifying compounds useful for the treatment of prostate cancer or evaluating the effectiveness of a prostate cancer treatment. For example, the effect of the compound on the fingerprint gene expression pattern normally displayed in connection with prostate cancer can be used to evaluate the efficacy of the compound as a treatment for prostate cancer or can, additionally, be used to monitor patients undergoing clinical evaluation for the treatment of prostate cancer.
A xe2x80x9cfingerprint pattern,xe2x80x9d as described herein, is the pattern generated when the expression pattern of a series (which can range from two up to all the fingerprint genes which exist for a given state) of fingerprint genes is determined. A fingerprint pattern can be used in the same diagnostic, prognostic and compound identification methods as the expression of a single fingerprint gene.
A xe2x80x9ctarget gene,xe2x80x9d as described herein, is a differentially expressed gene involved in prostate cancer such that modulation of the level of target gene expression or of target gene product activity can act to prevent and/or ameliorate symptoms of the prostate cancer. Compounds that modulate the expression of the target gene or the activity of the target gene product can be used in the treatment of prostate cancer. Still further, compounds that modulate the expression of the target gene or activity of the target gene product can be used in treatments to deter benign cells from developing into prostate cancer cells. Still further, compounds that modulate the expression of the target gene or activity of the target gene product can be used to design a preventive intervention in pre-neoplastic cells in individuals at high risk.